Technical field:

This invention relates to the field of pharmaceutical co crystals. More particularly, the present invention relates to synergistic pharmaceutical co crystals comprising soluble forms of broad-spectrum fluoroquinolone antibacterial agents namely Ciprofloxacin and Norfloxacin with small molecules that have unique physical properties and biological activity which differ from the active agent in pure form, to process for preparation of the same and also relates to pharmaceutical compositions comprising these synergistic co-crystals.

Background and prior art:

Even though co-crystals were known as early as 19th century, the pharmaceutical industry has recognized the potential for their applications only recently. Pharmaceutical co-crystals are crystalline molecular complexes containing therapeutic molecules. These co crystals represent emerging class of pharmaceutical materials offering the prospects of optimized physical properties.

The application of co-crystallization can further be extended to neutral molecules, amorphous compounds, to improve their physio-chemical properties. Further, these co-crystals have utility in imparting desirable physical properties and stability, which are otherwise not achievable for the pure active agent or in combination as a simple formulation using the excipients incorporated with the active agent.

WO/2004/078163 describes pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen.

WO/2005/055983 describes a method for preparation of mixed phase co-crystal composition, wherein the active agent and crystal lattice modifier are contained within the mixed phase co-crystal composition.

US20070026078 describes a pharmaceutical composition comprising a co-crystal of an API and a co-crystal former; wherein the API has at least one functional group selected from ether, thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid, phosphonic acid, phosphinic acid, sulfonic acid, amide, primary amine, secondary amine, ammonia, tertiary amine, sp2 amine, thiocyanate, cyanamide, oxime, nitrile diazo, organohalide, nitro, s-heterocyclic ring, thiophene, n-heterocyclic ring, pyrrole, o-heterocyclic ring, furan, epoxide, peroxide, hydroxamic acid, imidazole, pyridine and the co-crystal former has at least one functional group selected from amine, amide, pyridine, imidazole, indole, pyrrolidine, carbonyl, carboxyl, hydroxyl, phenol, sulfone, sulfonyl, mercapto and methyl thio, such that the API and co-crystal former are capable of co-crystallizing from a solution phase under crystallization conditions.

However, there are no reports of usage of co-crystals to enhance the efficacy of antibiotic. Fluroquinolones form a group of broad spectrum antibiotic. Ciprofloxacin and Norfloxacin come under the said group called fluroquinolones.

The mode of action of Ciprofloxacin depends upon blocking bacterial DNA replication by binding itself to an enzyme called DNA gyrase, thereby causing double-stranded breaks in the bacterial chromosome. The solubility of Ciprofloxacin is 0.08mg/ml and the biological half life is 4 hrs.

Similarly, Norfloxacin is an oral broad-spectrum fluoroquinolone antibacterial agent used in the treatment of urinary tract infections. It is also used to treat stomach infections. The mode of action of Norfloxacin involves inhibition of the A subunit of bacterial DNA gyrase, an enzyme which is essential for DNA replication. The biological half life of the drug is 3 to 4 hrs. The solubility of Norfloxacin is 0.24mg/ml.

There is ample literature available on the above mentioned antibacterial agents and the pharmaceutical compositions comprising the same. However, the poor solubility of the above mentioned actives results in poorer bioavailability of the same. Therefore, there is a need in the art to develop soluble forms of broad-spectrum fluoroquinolone antibacterial agents, such as Norfloxacin and Ciprofloxacin, to overcome the problem of bioavailability as well as to enhance the efficacy, by the synergistic action of API with the co-crystal former.

In the current invention, the inventors have achieved the norfloxacin and ciprofloxacin co-crystals using numerous co-crystal formers selected from the group consisting of phenolics, flavonoids, monoterpenes, aminoacids, alkaloids, vitamins, neutraceuticals, which works synergistically along with parent anti-bacterial compound, Norfloxacin, thus enhance the efficacy of the parent molecule in lower doses.

Summary of the invention:

In accordance with the above objective, the present invention provides synergistic pharmaceutical co-crystals of broad-spectrum fluoroquinolone antibacterial agents namely Ciprofloxacin and Norfloxacin in soluble forms. However, this invention encompasses all other fluroquinolone antibiotics selected from the group consisting of enoxacin, lomefloxacin, nadifloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, levofloxacin, pazufloxacin, sparfloxacin, osufloxacin, clinafloxacin, gemifloxacin, moxifloxacin, Getifloxacin and sitafloxacin.

The co-crystal approach of present invention further encompasses the fluroquinolone antibiotics which have been withdrawn from the market due to associated side effects, such as fleroxacin, grepafloxacin, trovafloxacin and alatrofloxacin as the cocrystal formation of these compounds may alter the biological properties and reduce the side effects accordingly.

In this application, the inventors have achieved the norfloxacin and ciprofloxacin co-crystals using numerous co-crystal formers selected from the group consisting of phenolics selected from the group consisting of eugenol, ferulic acid, isoferulic acid, resveratrol, Capsaicin, Chavibetol, Guaiacol,rosmarinic acid, anethole, chavicol, vanillin; flavonoids such as catechin hydrate, quercetin dihydrate chrysin, galangin, rutin, hesperidine, glycosides of quercetin, kaempferol, chrysin; monoterpenes such as geraniol, linalool, citral, camphor, menthol, ocimene, pinenes; aminoacids such as phenyl alanine, glutamic acid, glutamine, glycine; alkaloids such as nicotinic acid, piperine, Trigonelline, pilocarpene, atropine, Ephedrine; vitamins such as folic acid, pyridoxine,nicotinic acid, Pantothenic acid, tocoferol, biotin, ascorbic acid, and neutraceuticals such as caffeine, monosaccharides, di and tri saccharides, citric acid, hydroxy citric acid, and also other small molecules such as, cinnamic acid & its derivatives curcumin, vanillin, piperonyl alcohol and rosmarinic acid, adipic acid, Ajoene, alliin, lipoic acid, gallic acvid, proanthocyanines, zingiberene, isoflavones, cuminaldehyde, saponins(diosgenin, yamogenin, tigogenin)and rosmarinic acid.

According to the present invention, the co-crystals of Norfloxacin and Ciprofloxacin have been prepared using the above mentioned co-crystal formers. These co-crystals showed higher solubility, dissolution rates and also found to be stable under accelerated conditions and thus suitable in preparing pharmaceutical compositions.

Further, the inventors have conducted the studies of antibacterial activity (MIC) of the compounds of the invention on microorganisms such as S. aureus, E.faecalis, E.facium, E.coli, K.pn and P.aeru and surprisingly found that some of these compounds have shown the great synergy among the parent molecule and the small molecule, which has been used as co-crystal former. These co-crystals exhibit higher antibacterial activity even at lower concentration when compared to parent molecule thus indicating good synergy among parent anti-biotic and the co-crystal former, while, the other co-crystal formers enhanced their physio-chemical properties.

In a further aspect, the invention provides a process for preparing the compounds of the invention using grinding and simple crystallization method.

In another aspect, the invention provides synergistic pharmaceutical compositions comprising the composition of the invention as described below.

The phrase 'composition of the invention' herein means and includes the composition comprising 'Norfloxacin-cocrystals' and the composition comprising 'Ciprofloxacin co-crystals' as described according to the present invention.

In yet another aspect, the invention provides process for production of pharmaceutical preparation, wherein said process comprises providing fluroquinolones with any one of the co-crystal former as mentioned above; isolating co-crystal comprising fluroquinolones and co-crystal former and incorporating into pharmaceutical composition along with one or more suitable pharmaceutical carriers/excipients. Carriers/Excipients are added to the composition for variety of purposes. Dosage forms include solid dosage forms like tablets, powders, capsules, sachets, troches and lozenges, liquid dosage forms like syrups, suspensions and elixirs; ophthalmic dosage forms including, drops, ointments; as well as parenteral dosage forms. The dosage forms can also be prepared as sustained, controlled, modified and immediate dosage forms. The active ingredient (s) and excipients can be formulated into compositions and dosage forms according to methods known in the art.

In yet another aspect, the invention provides method for treating symptoms associated with various bacterial infections like, urinary tract infections, stomach infections, skin infections, eye infections, mycobacterial infections and chest infections which method comprises administering 'an effective amount' of the 'composition of invention ' to the subject suffering from said infections. The subject mentioned herein is human.

The invention further discloses use of the 'composition of the invention' in preparing the medicament intend to treat wide spectrum of bacterial infections selected from skin infections, chest infections, urinary tract infections, mycobacterial infections and gastro intestinal system infections.

Description of drawings:

Fig 1 shows the PXRD profile of Norfloxacin

Fig 2 shows the PXRD profile of cocrystal of Norfloxacin and eugenol

Fig 3 shows PXRD profile of cocrystal of Norfloxacin and ferulic acid

Fig 4 shows PXRD profile of cocrystal of Norfloxacin and isoferulic acid

Fig 5 shows the PXRD profile of Ciprofloxacin

Fig 6 shows the PXRD profile of cocrystal of Ciprofloxacin and eugenol

Fig 7 shows the PXRD profile of cocrystal of Ciprofloxacin and ferulic acid

Fig 8 shows the PXRD profile of cocrystal of Ciprofloxacin and isoferulic acid

Fig 9 shows the graphical representation of solubility of Norfloxacin and the cocrystals
prepared using eugenol (ILS-A1-01), ferulic acid (ILS-A1-03) and isoferulic acid (ILS-
Al-02)

Fig 10 shows the graphical representation of dissolution profile of Norfloxacin and the
cocrystals prepared using eugenol (ILS-A1-01), and isoferulic acid (ILS-A1-02).

Fig 11 shows the graphical representation of solubility of Ciprofloxacin and the
cocrystals prepared using eugenol (ILS-A2-01), ferulic acid (ILS-A2-03) and isoferulic
acid (ILS-A2-02)

Fig 12 shows the graphical representation of dissolution profile of Ciprofloxacin and the
cocrystals prepared using eugenol (ILS-A2-01), ferulic acid (ILS-A2-03) and isoferulic
acid (ILS-A2-02)

Fig 13 shows graphical presentation of equilibrium solubility of the Norfloxacin (ILS-
Al-04) and its cocrystals with quercetin dehydrate (ILS-A1-05) and citric acid(ILS-Al-
06)

Fig 14 shows DSC of Norfloxacin with citric acid

Fig 15 shows DSC of Norfloxacin with caffeine

Fig 16 shows DSC of Norfloxacin with eugenol

Fig 17 shows DSC of Norfloxacin with maleic acid

Detailed description of the invention:

The invention will now be described in detail in connection with certain preferred and optional embodiments; so that various aspects thereof may be more fully understood and appreciated.

The phrase 'composition of the invention' herein means and includes the composition comprising 'Norfloxacin-cocrystals' and the composition comprising 'Ciprofloxacin co-crystals' as described according to the present invention.

Thus, the present invention provides synergistic soluble forms of broad-spectrum fluoroquinolone antibacterial agent, namely Norfloxacin and Ciprofloxacin. Accordingly, the co-crystals of Norfloxacin and Ciprofloxacin have been provided using small molecules/co-crystal formers selected from the group consisting of phenolics, flavonoids, monoterpenes, aminoacids, alkaloids, vitamins and neutraceuticals. The co-crystals of Norfloxacin and Ciprofloxacin (fluoroquinolone antibiotic) prepared according to the present invention are having enhanced solubility, rate of dissolution. Further, these co-crystals have showed enhanced efficacy when compared to the parent antibiotics, Norfloxacin as well as Ciprofloxacin thus proving good synergy among the parent molecule and co-crystal former.

These small molecules/cocrystals formers may also be selected from the group comprising of antiseptic agents, anesthetic agents, anti-inflammatory agents, hypoglycsemic agents and anti-oxidants.

The co-crystal formers have been selected preferably from phenolics selected from the group consisting of eugenol, ferulic acid,isoferulic acid, resveratrol, Capsaicin, Chavibetol, Guaiacol rosmarinic acid, anethole, chavicol, vanillin; flavonoids such as catechin hydrate, quercetin dehydrate, kaempferol, chrysin, galangin, rutin, hesperidine, anthocyanidins, glycosides of quercetin, kaempferol, chrysin, galangin, anthocyanins; monoterpenes such as geraniol, linalool, citral, camphor, menthol, ocimene, pinenes; aminoacids such as phenyl alanine, glutamic acid, glutamine, glycine; alkaloids such as nicotinic acid, pipeline, Trigonelline, pilocarpene, atropine, Ephedrine; vitamins such as folic acid, pyridoxine, nicotinic acid, Pantothenic acid, tocoferol, biotin, ascorbic acid; neutraceuticals such as monosaccharides, disaccharides, trisaccharides, alditols, caffeine, lycopene, beta-carotene, hydroxycitric acid, citric acid and also other small molecules such as, cinnamic acid & its derivatives, adipic acid, citric acid, tartaric acid, curcumin, vanillin, piperonyl alcohol, Ajoene, alliin, lipoic acid, gallic acvid, proanthocyanines, zingiberene, isoflavones, cuminaldehyde, saponins(diosgenin, yamogenin, tigogenin)and rosmarinic acid.

According to preferred embodiment, the invention provides Norfloxacin co-crystals containing the co-crystal formers selected from phenolic like eugenol, ferulic acid, isoferulic acid, resveratrol, flavonoids such as catechin hydrate, quercetin dihydrate; monoterpenes such as geraniol, aminoacids such as phenyl alanine, glutamic acid, glutamine; alkaloids such as nicotinic acid, vitamins such as biotin, mono, di- & tri-saccharides such as D-glucose, alditols such as, Mannitol, and neutraceuticals such as caffeine and also other small molecules such as adipic acid, citric acid, tartaric acid, curcumin, glycine, vanillin, piperonyl alcohol and rosmarinic acid.

According to another preferred embodiment, the invention provides Ciprofloxacin co-crystals comprising crystal formers selected from eugenol, ferulic acid, isoferulic acid citric acid and tartaric acid.

The invention further provides a process for preparing the compounds of the present invention, which comprises hand grinding of active ingredient, fluoroquinolone and co-crystal former in 1 :1 ratio in mortar and pestle for 5 minutes for making the mixture homogenous. This mixture is further crystallized from suitable organic solvents selected from ethanol, methanol, isopropyl alcohol, dimethyl formamide, acetonitrile, dimethyl formamide, acetonitrile, tetrahydrofuran or dioxane and the like, under ambient conditions. Crystallization is generally accomplished by heating the solution over hot plate at 50-100 °C and slow cooling of saturated solution thereafter. Normally co-crystals appear within 2 to 3 days.

The formation of co-crystal or salt is confirmed by IR spectral data, powder X-ray profile and DSC thermo gram. Further, the formation of co-crystals is confirmed by melting point of the same. The comparison of melting points of Ciprofloxacin and co-crystal formers vis-a-vis cocrystals comprising Ciprofloxacin are given below in table 1.

The comparison of melting points of Norfloxacin and co-crystal formers with co-crystals comprising Norfloxacin according to the present invention are given below in table 2

DSC studies (for Maleic acid, Eugenol, Caffeine & Citric Acid) also indicated the formation of a cocrystal, as a single sharp peak at a different temperature from its parent compositions was observed

Experiment of co-crystal formation was carried out by solvent assisted (acetonitrile) grinding of Norfloxacin/Ciprofloxacin with the co-crystal agent for 15 minutes and later drying to evaporate the solvent. Grinded mixture was further tested for the co-crystal formation by means of IR spectrum.

The compounds of the invention, further characterized using IR Spectrum and the comparative values of Ciprofloxacin vis-a-vis cocrystals of the same, prepared using eugenol, isoferulic acid and ferulic acid, are provided below in table 3.

Accordingly, the compounds of the invention comprising Norfloxacin-co-crystals, further characterized using IR Spectrum and the comparative values of Norfloxacin vis-a-vis co-crystals of the same, prepared using resveratrol, catechin hydrate, quercetin dihydrate, geraniol, phenyl alanine, glutamic acid, glutamine, nicotinic acid, biotin, caffeine, adipic acid, citric acid, curcumin, glycine, vanillin, piperonyl alcohol and rosmarinic acid are provided below in table 4.

The 'compounds of the invention' are finely grinded and passed through standard mesh filter and particles with 75-180 micron are tested for their solubility and dissolution profile.

The solubility of the Norfloxacin/Ciprofloxacin co-crystals prepared according to the present invention is compared with the parent molecule and found that the solubility of most of the co-crystals is greater than the parent molecule. However, very few of the co-crystals prepared according to the present invention exhibits lower solubility compared to parent molecules, Norfloxacin/Ciprofloxacin as discussed below in tables 5 to 7.

The solubility of Ciprofloxacin co-crystals prepared according to the present invention is compared with the parent molecule and found that the solubility of the co-crystal formed with eugenol, isoferulic acid and ferulic acid is 11 times, 20 times and 8 times greater than the parent molecule, respectively. The comparative solubility of Ciprofloxacin and co-crystals of the same, according to the present invention is also provided below in table

Similarly the solubility of the Norfloxacin co-crystals prepared according to the present invention is compared with the parent molecule and found that the solubility of the co-crystal formed with eugenol, isoferulic acid and ferulic acid is 3 times, 6 times and 5 times greater than the parent molecule, respectively. The comparative solubility of Norfloxacin and co-crystals of the same according to the present invention is provided below in table 6:

Accordingly, the invention further provides equilibrium solubility of Norfloxacin and compared the same with its co-crystals of quercetin dihydrate and citric acid. When
compared with Norfloxacin, the co-crystal of Norfloxacin with citric acid has shown improved solubility, while co-crystal of quercetin dihydrate has shown the decrease in solubility as shown in table 7.

The dissolution studies indicated that all these compounds are having enhanced dissolution rate when compared to the parent molecules as discussed in figs 10 and 12.

Further, the compounds of the invention have been found to be stable under the accelerated studies.

The antibacterial activity (MIC) of the compounds of the invention has been conducted on microorganisms such as S. aureus, E. faecalis, E. factum, E. coli, K. pn and Y.aeru and found that all these compounds are having high antibacterial activity even at lower concentration when compared to parent molecule indicating good synergy among crystal former and the parent molecule. The antibacterial activity has been given in table 8 below.


Note: In the parentheses of the first column of the table, the actual amount of the API used (Norfloxacin or Ciprofloxacin). Though the amount of the standard compound is lower in the cocrystals; however, the activity is either the same or enhanced.

It is clear from the above table that with lesser amounts of the API either the same effect (same log value) or a better effect is observed thus proving that the cocrystals of the present invention have enhanced pharmacological action over the parent molecules, i.e Norfloxacin and Ciprofloxacin. Further, the Cocrystal formers are also acting synergistically with the APIs rendering enhanced pharmacological effect.

As these co-crystals, exhibit either the same activity or enhanced activity compared to standard compound even at much lower doses confirming the industrial applicability of the present invention.

The results described herein above, conclusively proves the introduction of synergy in the co-crystals by combining the antibiotics with the said co-crystal formers which act not only as co-Crystal formers but also contribute to enhance the efficacy of the antibiotic by their formation of the co-crystals with the parent antibiotic.

The changes in properties of the active agent when prepared as co-crystals are particularly advantageous for the delivery of poorly soluble active agent in lower amounts. Therefore, in yet another aspect, the invention provides synergistic pharmaceutical compositions comprising the co-crystals of fluroquinolone compounds selected Norfloxacin and Ciprofloxacin.

Therefore, in another embodiment, the invention provides process for production of pharmaceutical preparation, wherein said process comprises providing Ciprofloxacin with any one of the co-crystal former as mentioned above; isolating co-crystal comprising Ciprofloxacin and co-crystal former and incorporating into pharmaceutical composition along with one or more suitable pharmaceutical carriers/excipients.

Similarly, in yet another embodiment, the invention provides process for production of pharmaceutical preparation, wherein said process comprises providing Norfloxacin with any one of the co-crystal former as mentioned above; isolating co-crystal comprising Norfloxacin and co-crystal former and incorporating into pharmaceutical composition along with one or more suitable pharmaceutical carriers/excipients.

Carriers/excipients are added to the composition for variety of purposes. Dosage forms include solid dosage forms like tablets, powders, capsules, sachets, troches and lozenges as well as liquid syrups, suspensions and elixirs. Dosage forms include solid dosage forms like tablets, powders, capsules, sachets, troches and lozenges, liquid dosage forms like syrups, suspensions and elixirs; ophthalmic dosage forms including, drops, ointments; as well as parenteral dosage forms The dosage forms can also be prepared as sustained, controlled, modified and immediate dosage forms. The active ingredient (s) and excipients can be formulated into compositions and dosage forms according to methods known in the art.

The quantity of the compound used in pharmaceutical compositions of the present invention will vary depending upon the body weight of the patient and the mode of administration and can be of any effective amount to achieve the desired therapeutic effect.

In a further embodiment, the present invention provides a method for treating symptoms associated with urinary tract infections, mycobacterial infections as well as stomach infections which method comprises administering 'an effective amount' of the 'composition of invention comprising Norfloxacin-cocrystals' to the subject suffering from urinary tract infections, mycobacterial infections as well as stomach infections for a period of up to 3 to 10 days. The subject mentioned herein is human.

The 'urinary tract infections' as described above including cystitis (inflammation of the inner lining of the bladder caused by a bacterial infection), prostatitis (inflammation of the prostate gland), and certain sexually transmitted diseases, such as gonorrhea.

The 'effective amount' as described above means and includes the amount required to treat/alleviate the severity of symptoms associated with this ailments as decided by the persons of ordinary skill in the art.

In yet another preferred embodiment, the present invention provides method for treating urinary tract infections as well as stomach infections using the inventive composition. The compositions of the present invention can be administered upto 600 to 800 milligrams per day. 300 to 400 milligrams should be taken twice a day for 3 to 10 days, depending upon the kind of bacteria causing the infection. Further, the treatment may extend up to three weeks if the subject is suffering with severe infective conditions as can be decided by the persons of ordinary skilled in the art. People with impaired kidney function may take 300 to 400 milligrams once a day for 3 to 10 days. However, the recommended dose of administration is twice a day.

The composition of the invention comprising Norfloxacin co-crystals can also be used to treat bacterial infections of eye. The administration of effective amount can be decided by the persons of ordinary skilled in the art.

The composition of the invention comprising Norfloxacin co-crystals can also be used to treat bacterial infections parenterally. The administration of effective amount can be decided by the persons of ordinary skilled in the art.

In another embodiment, the present invention provides a method for treating symptoms associated with skin infections, chest infections, urinary tract infections, gastro-intestinal system infections and mycobacterial infections, which method comprises administering 'an effective amount' of the 'composition of invention comprising Ciprofloxacin-cocrystals' to the subject suffering from said infections for a period of up to 3 to 10 days.

The subject mentioned herein is human.

In yet another preferred embodiment, the present invention provides method for treating urinary tract infections as well as gastro-intestinal infections using the inventive composition comprising Ciprofloxacin-co-crystals. The compositions of the present invention can be administered upto 200 to 1000 milligrams per day. 200 to 500 milligrams should be taken twice a day for 3 to 10 days, depending upon the kind of bacteria causing the infection as can be decided by the persons of ordinary skilled in the art.

The composition of the invention comprising Ciprofloxacin co-crystals can also be used to treat bacterial infections of eye. The administration of effective amount can be decided by the persons of ordinary skilled in the art.

The composition of the invention comprising Ciprofloxacin co-crystals can also be used to treat bacterial infections parenterally. The administration of effective amount can be decided by the persons of ordinary skilled in the art.

The composition of the invention preferably administered along with one or more pharmaceutical excipients(s)/ carrier(s).

The oral administration may be accomplished by ingesting the composition preferably in a form of tablet/capsule/liquid with a glass of water. The other dosage forms like hard gelatin capsules, powders, liquid capsules, syrups, suspensions, elixirs are also equally good modes of oral administration.

In another embodiment, the invention discloses use of the composition of the invention comprising Norfloxacin co-crystals in preparing the medicament intend to treat wide spectrum of bacterial infections selected from urinary tract infections, eye infections, mycobacterial infections as well as stomach infections.

In yet another embodiment, the invention discloses use of the composition of the invention comprising Ciprofloxacin co-crystals in preparing the medicament intend to treat wide spectrum of bacterial infections selected from skin infections, chest infections, urinary tract infections, eye infections, mycobacterial infections and gastro-intestinal system infections.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for the purpose of illustrative discussion of preferred embodiments of the invention.

Experimental:

Co-crystals of the present invention are prepared by using the following method.
Materials used:

leq drug

1.05eq co-crystal or salt former (1:1 ratio)

Co-crystal former purchased (Loba chemie Pvt. Ltd., India) or prepared using reported
procedure in literature.

X-ray powder diffractometry:

Powder data were collected on PANalytical, X'Pert PRO X-ray powder diffractometer
using a parallel beam of monochromated Cu-Ka radiation (X = 1.5418 A) and an
X'Celerator detector at 45 kV voltage and 40 mA Current. Diffraction patterns were
collected over the 20 range 3-45°.

Single crystal analysis

Single Crystal data were collected on Single Crystal Bruker Smart Apeax CCD X-
Difractometer (Molbdenum K« radiation, X = 0.71073 A0).

Thermal Analysis:

DSC was performed on Mettler Toledo DSC 822e module and TG on TGA/SDTA 85le module. Data were manipulated in the STAR software system. Samples were placed in crimped but vented aluminum pans for DSC (4-6 mg) and in open alumina cups for TG (8-14 mg). The temperature range was 30-300 °C @ 2 °C min-1 for DSC and @ 10 °C min-1 for TG. Samples were purged by a stream of dry N2 flowing @ 150 mL min-1 for
DSC and 50 mL min"1 for TG.

Particle Size:

Finely grinded material was passed through standard mesh filter and particle with 75-180 micron were used for solubility and dissolution profile experiments.

Solubility:

The solubility studies for co-crystals and salts were performed according to Higuchi and Connor's method with some variations. Excess amounts (100 mg) of the samples were suspended in 10 mL of water in round bottom flask. Solutions were stirred at 300 rpm using a magnetic stirrer. After 72 h, the suspensions were filtered through a paper filter (Whatman 40)) and filtered aliquots were sufficiently diluted, the absorbance of the samples were measured at 276 nm, and the values were normalized for API. Finally, the concentration of API after 72 h (apparent aqueous solubility) in each sample was determined from the previously made standard graph. A standard graph was made by measuring the absorbance of varied concentrations of API in water using a UV spectrophotometer (Nanodrop UV/vis spectrometer) at Amax 276 nm.

Dissolution Rate:

Co-crystal or salt taken (2 mole)in 50 ml round bottom flask and 50 ml of nano pure water added over it. This solution was stirred at 300 rpm. 5 ml of solution was taken out at 5, 10, 30, 60 and 120 minutes interval and filtered through Whatman 40 filter paper. The filtrate was diluted by 10 times and UV absorption was measured. The absorbance was plotted in origin to get dissolution profile curve.

Example 1

General methods of preparation of cocrystals:

Grinding: API and co-crystal former (salt former)were taken in mortar pastle (1:1 ratio)
and hand grinded for 5 minutes for making it homogenous.

Crystallization: The resultant mixture was crystallized in solvents selected from ethanol,
methanol, isopropyl alcohol, dimethyl formamide, acetonitrile, dimethyl formamide-
acetonitrile, tetrahydrofuran, or dioxane under ambient conditions. Crystallization was
accomplished by heating the solution over hot plate at 50-100 °C and then the saturated
solution was slowly cooled. Generally cocrystals appear in 2-3 days. The formation of
these co-crystal or salt was confirmed by powder X-ray powder difractometry. These
cocrystals were further characterized by thermal analysis.

Example 2

Preparation of co-crystal of norfloxacin with Ferulic acid:
Grinding:

Norfloxacin 31.9mg(0.1milli mole) and 19.4 mg(0.1milli mole) of ferulic acid were grinded together along with 2 drops of (0.2ml) of methanol to make it homogeneous mixture. The grinding was carried out for a period of 15 min. Crystallization:
The resultant mixture was crystallized in solvents selected from methanol (10 ml) under ambient conditions. Crystallization was accomplished by heating the solution over hot plate at 50-100 °C and then the saturated solution was slowly cooled. The co-crystals have appeared after 48 hours.

Example 3

Preparation of co-crystal of Ciprofloxacin with Ferulic acid:
Grinding:

Ciprofloxacin 31.9mg(0.1milli mole) and 19.4 mg(0.1milli mole) of ferulic acid were grinded together along with 2 drops of (0.2ml) of methanol to make it homogeneous mixture. The grinding was carried out for a period of 15 min. Crystallization:

The resultant mixture was crystallized in solvents selected from methanol (10 ml) under ambient conditions. Crystallization was accomplished by heating the solution over hot plate at 50-100 °C and then the saturated solution was slowly cooled. The co-crystals have appeared after 48 hours.

Example 4

Preparation of co-crystal of norfloxacin with isoferulic acid:

Grinding:

Norfloxacin 31.9mg(0.1milli mole) and 19.4 mg(0.1milli mole) of isoferulic acid were grinded together along with 2 drops of (0.2ml) of methanol to make it homogeneous mixture. The grinding was carried out for a period of 15 min. Crystallization:

The resultant mixture was crystallized in solvents selected from methanol (10 ml) under ambient conditions. Crystallization was accomplished by heating the solution over hot plate at 50-100 °C and then the saturated solution was slowly cooled. The co-crystals have appeared after 48 hours.

Example 5

Preparation of co-crystal of norfloxacin with Eugenol:

Grinding:

Norfloxacin 31.9mg(0.1milli mole) and 19.4 mg(0.1milli mole) of eugenol were grinded together along with 2 drops of (0.2ml) of methanol to make it homogeneous mixture. The grinding was carried out for a period of 15 min. Crystallization:

The resultant mixture was crystallized in solvents selected from methanol (10 ml) under ambient conditions. Crystallization was accomplished by heating the solution over hot plate at 50-100 °C and then the saturated solution was slowly cooled. The co-crystals have appeared after 48 hours.

Example 6

Preparation of co-crystal of norfloxacin with Eugenol:

Grinding:

Ciprofloxacin 31.9mg(0.1milli mole) and 19.4 mg(0.1milli mole) of Eugenol were grinded together along with 2 drops of (0.2ml) of methanol to make it homogeneous mixture. The grinding was carried out for a period of 15 min. Crystallization:
The resultant mixture was crystallized in solvents selected from methanol (10 ml) under ambient conditions. Crystallization was accomplished by heating the solution over hot plate at 50-100 °C and then the saturated solution was slowly cooled. The co-crystals have appeared after 48 hours.

Example 7

Preparation of co-crystal of Ciprofloxacin with Citric acid:

Grinding:

Ciprofloxacin 31.9mg(0.1milli mole) and 19.4 mg(0.1milli mole) of Citric acid were
grinded together along with 2 drops of (0.2ml) of methanol to make it homogeneous
mixture. The grinding was carried out for a period of 15 min.

Crystallization:

The resultant mixture was crystallized in solvents selected from methanol (10 ml) under
ambient conditions. Crystallization was accomplished by heating the solution over hot
plate at 50-100 °C and then the saturated solution was slowly cooled. The co-crystals
have appeared after 48 hours.

Square network of Citric acid molecules which are connected to Ciprofloxacin molecule
is as shown below: (Single X-ray crystallographic pattern)

In single crystal data, the well known supramolecular hetero synthons (pyridine - acid) were observed, indicating the interaction between the ciprofloxacin molecules and the citric acid molecules. Also, Citric Acid molecules formed a cage in which the ciprofloxacin molecules got included.

H-Bonding between Ciprofloxacin and Citric acid is shown in table-9


The above table confirms the presence of hydrogen bonding between Ciprofloxacin and citric acid in a co-crystal comprising of Ciprofloxacin and citric acid

Example 8

Preparation of co-crystal of Ciprofloxacin with tartaric acid:

Grinding:

Ciprofloxacin 31.9mg(0.1milli mole) and 19.4 mg(0.1milli mole) of Tartaric acid were
grinded together along with 2 drops of (0.2ml) of methanol to make it homogeneous
mixture. The grinding was carried out for a period of 15 min.

Crystallization:

The resultant mixture was crystallized in solvents selected from methanol (10 ml) under
ambient conditions. Crystallization was accomplished by heating the solution over hot
plate at 50-100 °C and then the saturated solution was slowly cooled. The co-crystals
have appeared after 48 hours. The Single X-ray crystallographic pattern is as shown
below:

In single crystal data, the well known supramolecular hetero synthons (pyridine - acid) were observed, indicating the interaction between the ciprofloxacin molecules and the tartaric acid molecules. Also, tartaric Acid molecules formed a cage in which the ciprofloxacin molecules got included.

H-Bonding between Ciprofloxacin and Tartaric acid is shown in table-10

The above table confirms the presence of hydrogen bonding between Ciprofloxacin and
Tartaric acid in cocrystal comprising of Ciprofloxacin and tartaric acid.

Similarly other co-crystals of Norfloxacin and Ciprofloxacin are prepared and characterized.

Example 9:

Pharmaceutical composition comprising co-crystal of Norfloxacin- isoferulic acid
The co-crystal of Norfloxacin-isoferulic acid is formulated using starch, Magnesium stearate as immediate release dosage form using conventional process.

Example 10:

Pharmaceutical composition comprising co-crystal of Ciprofloxacin-Eugenol

The co-crystal of Ciprofloxacin-Eugenol is formulated using HPMC, starch, Magnesium stearate as sustained release dosage form using conventional process.

It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

We claim,

1. Synergistic, soluble forms of pharmaceutical co-crystal compositions of Fluroquinolone compounds comprising at least one fluroquinolone compound and a co-crystal former.

2. The pharmaceutical co-crystal compositions as claimed in claim 1, wherein, said Fluroquinolone compound is selected from the group comprising of Ciprofloxacin, Norfloxacin, enoxacin, lomefloxacin, nadifloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, levofloxacin, pazufloxacin, sparfloxacin, osufloxacin, clinafloxacin, gemifloxacin, moxifloxacin, Getifloxacin and sitafloxacin.

3. The pharmaceutical co-crystals compositions as claimed in claim 1, wherein said co-crystal former is selected from the group comprising of phenolics selected from the group consisting of resveratrol, Capsaicin, Chavibetol, Guaiacol, rosmarinic acid, anethole, chavicol, vanillin; flavonoids such as catechin hydrate, quercetin dihydrate chrysin, galangin, rutin, hesperidine; glycosides of quercetin, kaempferol, chrysin; monoterpenes such as geraniol, linalool, citral, camphor, menthol, ocimene, pinenes; aminoacids such as phenyl alanine, glutamic acid, glutamine, glycine; alkaloids such as nicotinic acid, piperine, Trigonelline, pilocarpene, atropine, Ephedrine; vitamins such as folic acid, pyridoxine, nicotinic acid, Pantothenic acid, tocoferol, biotin, ascorbic acid; neutraceuticals such as caffeine, monosaccharides, di and tri saccharides, citric acid, tartaric acid, hydroxy citric acid, and also other small molecules such as, cinnamic acid & its derivatives, curcumin, vanillin, piperonyl alcohol, rosmarinic acid, adipic acid, Ajoene, alliin, lipoic acid, gallic acvid, proanthocyanines, zingiberene, isoflavones, cuminaldehyde, saponins(diosgenin, yamogenin, tigogenin)and rosmarinic acid.

4. The pharmaceutical co-crystals compositions as claimed in claim 1, wherein said fluroquinolone compound is Norfloxacin.

5. The pharmaceutical co-crystals compositions as claimed in claim 1, wherein said fluroquinolone compound is ciprofloxacin.

6. The pharmaceutical co-crystals compositions as claimed in claim 4, wherein said co-crystal is selected from the group comprising of Norfloxacin and eugenol; Norfloxacin and ferulic acid; Norfloxacin and isoferulic acid; Norfloxacin and adipic acid; Norfloxacin and biotin; Norfloxacin and caffeine; Norfloxacin and catechin hydrate; Norfloxacin and citric acid; Norfloxacin and curcumin; Norfloxacin and geraniol; Norfloxacin and glutamic acid; Norfloxacin and glutamine; Norfloxacin and glycine; Norfloxacin and vanillin; Norfloxacin and nicotinic acid; Norfloxacin and phenyl alanine; Norfloxacin and piperonyl alcohol; Norfloxacin and quercitine dehydrate; Norfloxacin
and resveratrol; or Norfloxacin and rosmarinic acid;

7. The pharmaceutical co-crystals as claimed in claim 5, wherein said co-crystal is selected from the group comprising of Ciprofloxacin and eugenol; Ciprofloxacin and ferulic acid, Ciprofloxacin and isoferulic acid, Ciprofloxacin and citric acid, Ciprofloxacin and tartaric acid.

8. The pharmaceutical co-crystal composition according to claim 1, further comprising a pharmaceutically acceptable diluent, excipient or carrier.

9. A process for preparing a pharmaceutical co-crystal composition according to claim 8, comprising (a) hand grinding of fluoroquinoline compound and cocrystal former in 1 :1 ratio in mortar pestle for 5 minutes for making the mixture homogenous; (b) crystallizing the homogenous mixture obtained in step (a) from suitable organic solvents selected from ethanol, methanol, isopropyl alcohol, dimethyl formamide, acetonitrile, dimethyl formamide- acetonitrile, tetrahydrofuran, dioxane under ambient to reflux conditions; (c) incorporating the co-crystals thus obtained in step (b) into a pharmaceutical composition using one or more suitable carriers/excipients.

10. Method for treating symptoms associated with urinary tract infections, stomach infections, mycobacterial infections as well as eye infections, which method comprises administering 'an effective amount' of the 'Norfloxacin-cocrystals' according to claim 6 to the subject suffering from urinary tract infections stomach infections, mycobacterial infections as well as eye infections.

11. Method for treating symptoms associated with skin infections, chest infections, urinary tract infections, gastro-intestinal infections, mycobacterial infections as well as eye infections, which method comprises administering 'an effective amount' of the 'Ciprofloxacin-cocrystals' according to claim 7 to the subject suffering from skin infections, chest infections, urinary tract infections, gastrointestinal infections, mycobacterial infections as well as eye infections.

12. The method according to claim 10 or 11, wherein said subject is human.

13. Use of the composition comprising Norfloxacin co-crystals according to claim 6 in preparing the medicament intend to treat wide spectrum of bacterial infections selected from urinary tract infections, eye infections, mycobacterial infections as well as stomach infections.

14. Use of the composition comprising Ciprofloxacin co-crystals according to claim 7, in preparing the medicament intend to treat wide spectrum of bacterial infections selected from skin infections, chest infections, urinary tract infections, eye infections, mycobacterial infections and gastro-intestinal system infections.